Sleep-deprived women have higher rates of cardiovascular disease, obesity, and metabolic dysregulation than do sleep-deprived men. The influences of sex on the ability to recover from sleep loss may underlie these increased risks for morbidity in women. Identification of the factors that are responsible for sex differences in the ability to recover from sleep loss is therefore critical to reducing, and someday eliminating, this gender disparity in sleep health. We have shown that sex differences in the daily sleep amount of mice are dependent on circulating reproductive hormones and that the ability to recover from sleep loss by increasing sleep amount and altering SWA is relatively insensitive to these hormones. This finding led us to hypothesize that sex chromosomes directly influence the ability to recover from sleep loss. Human studies are limited in their ability to examine: 1) the contributions of genetic and phenotypic sex to gender differences in sleep traits and 2) polysomnographic sleep responses to extended chronic sleep loss in men and women. These limitations underscore the need for effective animal models to determine whether sex-specific genetic and hormonal interactions influence sleep opportunities during and after chronic sleep loss. An exciting mouse model of genetic sex now provides an opportunity to examine the discrete contributions of sex chromosomes to sleep regulatory mechanisms. In this four core genotype mouse model of genetic sex, the sex chromosome complement is the opposite of gonadal and phenotypic sex. In addition, refinements in the ability to obtain intracortical recording of slow wave activity (SWA) in active rodents now provide a unique opportunity to determine the regulatory influences of sex on homeostatic sleep responses. By employing a more rigid electrophysiological measurement of SWA and by examining whether sex chromosome complement has influences on the ability of chronic sleep loss to disrupt sleep regulatory mechanisms, these studies will determine the nature of sex differences in sleep alterations caused by chronic sleep loss and increase understanding of the mechanisms underlying those differences. PUBLIC HEALTH RELEVANCE: Sleep is emerging as an important health issue. In today's twenty-four hour society, women suffer disproportionately from the negative health consequences associated with chronic sleep loss. Since negative sleep responses to daily challenges may be a predisposing factor for morbidity, it is important to determine the influences of biological sex on the ability to tolerate chronic sleep loss. These experiments use EEG/LFP/EMG recording in mutant mouse models to determine whether genetic, gonadal, and phenotypic determinants of sex are predisposing factors for sleep dysregulation during and after chronic sleep loss.